Devices and methods for promoting transcutaneous movement of substances

ABSTRACT

A non-invasive method of enhancing the permeability of the skin to a biologically active permeant or compound is described utilizing a combination of sonophoresis and chemical enhancers. Synergism brought simultaneously applying iontophoresis, electroporation, mechanical vibrations and magnetophoresis is used to optimize the transcutaneous active permeation of compounds, considerably lowering the time of treatment.The method is intended also for, among others, the non-invasive painless treatment of cellulitis, localized fat stretch marks and flacid skin.

BACKGROUND OF THE INVENTION

This invention relates generally to the field of compound delivery forobtaining both local and systemic results. More particularly, it relatesto a non-invasive method of compound delivery through the epidermis bymeans of increasing the permeability of skin through the use of chemicalenhancers and sonophoresis and the synergetic simultaneous use ofiontophoresis, electroporation, mechanical vibrations andmagnetophoresis for optimizing transcutaneous compound delivery into thebody.

The human skin has barrier properties and stratum corneum is mostlyresponsible for them, thus it is exactly the statum corneum, the outerhorny layer of the skin, that imposes the greatest barrier totranscutaneous flux of compounds into the body.

The low permeability attributed to the stratum corneum, a complexstructure comprised of multi-layered compact keratinized cells; lowpermeability is due to dead cells filled with keratin fibers(keratinocytes) surrounded by highly-ordered structure of lipid bilayers(Flynn, G. L., In Percutaneous Absorption: Mechanisms-Methodology-DrugDelivery.; Bronaugh, R. L., Maibach, H. I. (Ed), pages 27-53, MarcelDekker, New York, 1989).

The stratum corneum hasn't constant thickness, since it depends on eachparticular area, being thinner in areas subject to folds and muchthicker in the hands palms and feet soles, is a very resistantwaterproof membrane that both protects the body from invasion byexterior substances and the outward migration of fluids and dissolvedmolecules and creates a mechanical and biological shield between theenvironment and the interior of the body. The stratum corneum iscontinuously renewed by shedding of dead cells during desquamation andthe formation of new corneum cells by the keratinization process.

Considering the permeation of compounds with non-charged molecules intothe skin the flux of said compound across the epidermis is controlled byFick's First Law which states that this flux depends on the diffusioncoefficient and on the gradient of concentration of the compound. Oneimportant issue to be remebered is that the diffusion coefficient isstrongly dependent on the degree of hydration of the skin, significantlyincreasing with it.

Therefore one of the ways of enhancing the flux of compounds into thebody is through the so-called penetration or chemical enhancers whichincrease the coefficient of diffusion of the stratum corneum and may beassociated with sonophoresis, that is, ultrasound energy.

From the physical standpoint ultrasound waves have been defined asmechanical pressure waves with frequencies above 20 KHz, H. Lutz et al.,Manual Of Ultrasound 3-12 (1984), are generated by either natural orsynthetic materials that show the so-called piezoelectric property,meaning that these materials both generate an electric field whenmechanically stressed (direct piezoelectric effect) and also generate amechanical force when an electric field is conveniently applied to them(inverse piezoelectric effect).

These properties have been first established by Pierre and Jacques Curiewho have observed their ocurrence in natural materials like the Rochellesalt;however in our days synthetic piezoceramic materials are preferredinstead due to their more stable properties since they are nothygroscopic and also to the possibility of being manufactured in anyshape, allowing a lot of different applications.

Ultrasound has also been used to enhance permeability of the skin andsynthetic membranes to compounds and other molecules and its use toincrease the permeability of the skin to compound molecules has beencalled sonophoresis or phonophoresis meaning transportation throughsound like waves.

U.S. Pat. No. 4,309,989 to Fahim describes a method of topicallyapplying an effective medication in an emulsion coupling agent byultrasound. More particularly, a method of treating a skin condition byapplying a medication in an emulsion coupling agent and massaging itinto the affected area with ultrasonic vibrations thereby causing themedication to penetrate into the skin. Specifically, a method andcomposition for the treatment of Herpes Simplex Type 1 and Type 2lesions. Also specifically, a method and composition for the treatmentof demidox mites. U.S. Pat. No. 4,372,296 to Fahim similarly describestreatment of acnes by topical application of zinc sulfate and ascorbicacid in a coupling agent.

U.S. Pat. No. 4,767,402 to Kost et al. discloses a method usingultrasound to enhance permeation of molecules through the skin and intothe blood stream, at a controlled rate. Depending on the compound beinginfused through the skin, the rate of permeation is increased as well asthe efficiency of transfer. Drugs which may not be effective under otherconditions, for example, due to degradation within the gastrointestinaltract, can be effectively conveyed transdermally into the circulatorysystem by means of ultrasound.Ultrasound is used in the frequency rangeof between 20 KHz and 10 MHz, the intensity ranging between 0 and 3W/cm.sup.2. The molecules are either incorporated in a coupling agentor, alternatively, applied through a transdermal patch.

U.S. Pat. No. 4,780,212 to Kost et al. teaches use time, intensity, andfrequency control to regulate the permeability of molecules throughpolymer and biological membranes. Further, the choice of solvents andmedia containing the molecules also affects permeation of the moleculesthrough the membranes.

U.S. Pat. No. 4,821,740 to Tachibana et al. discloses an endermicapplication kit for external medicines, which comprises adrug-containing layer as provided near an ultrasonic oscillator. The kitincludes a cylindrical fixed-type or portable-type and a flatregular-type or adhesive-type, and the adhesive-type may be flexible andelastic. The drug absorption is ensured by the action of the ultrasonicwaves from the oscillator and the drug release can be controlled byvarying the ultrasonic wave output from the oscillator.

U.S. Pat. No. 5,007,438 to Tachibana et al. is described an applicationkit in which a layer of medication and an ultrasound transducer aredisposed within an enclosure. The transducer may be battery powered.Ultrasound causes the medication to move from the device to the skin andthen the ultrasound energy can be varied to control the rate ofadministration through the skin.

U.S. Pat. No. 5,115,805 to Bommannan et al. discloses a method forenhancing the permeability of the skin or other biological membrane to amaterial such as a drug is disclosed. In the method, the drug isdelivered in conjunction with ultrasound having a frequency of aboveabout 10 MHz. The method may also be used in conjunction with chemicalpermeation enhancers and/or with iontophoresis. It is informed but notshown that chemical penetration enhancers and/or iontophoresis could beused in connection with the ultrasound treatment.

U.S. Pat. No. 5,444,611 to Eppstein et al. describes a method ofenhancing the permeability of the skin or mucosa to a biologicallyactive permeant or drug utilizing ultrasound or ultrasound plus achemical enhancer.

Ultrasound can be modulated and frequency modulated ultrasound from highto low frequency can develop a local pressure gradient directed into thebody.The method is also useful as a means for application of a tatoo bynininvasively delivering a pigment through the skin surface. Due to thecompleteness of that disclosure, the information and terminologyutilized therein are incorporated herein by reference.

U.S. Pat. No. 6,041,253 to Kost et al. describes a method fortransdermal transport of molecules during sonophoresis (delivery orextraction) further enhanced by application of an electric field, forexample electroporation of iontophoresis.This method provides higherdrug transdermal fluxes,allows rapid control of transdermal fluxes,andallows drug delivery or analyte extraction at lower ultrasoundintensities than when ultrasound is applied in the absence of anelectric field. Due to the completeness of that disclosure, theinformation and terminology utilized therein are incorporated herein byreference.

U.S. Pat. No. 6,234,990 to Rowe et al. discloses methods and devices forapplication of ultrasound to a small area of skin for enhancingtransdermal transport.An ultrasound beam having a first focal diameteris channelled into a beam having a second,smaller diameter withoutsubstantial loss of energy.A two step noninvasive method involvesapplication of ultrasound to increase skin permeability and removal ofultrasound followed by transdermal transport that can be furtherenhanced using a physical enhancer. Due to the completeness of thatdisclosure, the information and terminology utilized therein areincorporated herein by reference.

Many other references teach use of ultrasound to deliver drugs throughthe skin including Do Levy et al., 83 J. Clin. Invest. 2074 (1989); P.Tyle & P. Agrawala, 6 Pharmaceutical Res. 355 (1989); F. L. Henley,65^(th) Annual Conference of the American Physical TherapyAssociation,Anhaheim,Calif.(1990);H. Benson et al., 8 PharmaceuticalRes. 1991);D. Bommannan et al., 9 Pharmaceutical Res. 559 (1992); K.Tachibana, 9 Pharmaceutical Res. 952 (1992);T. Wong,Proceedings of theJoint Congress of the American Physical TherapyAssociation,Toronto,Ontario,Canada(1994);N. N. Byl,Physical Therapy,Volume 75, Number 6, (1995).

Many authors report the success of application of sonophoresis, J.Griffin & J. Touchstone, 42 Am. J. Phys. Med. 77 (1963); J. Griffin etal., 44 Am. J. Phys. Med. 20 (1965); J. Griffin et al., 47 Phys. Ther.594 (1967); J. Davick et al., 68 Phys. Ther. 1672 (1988);D. Bommannan etal., 9 Pharm. Res. 559 (1992), while others have obtained negativeresults, J. McElnay et al., 20 Br. J. Clin. Pharmacol. 4221 (1985); H.Pratzel et al., 13 J. Rheumatol. 1122 (1986); H. Benson et al., 69 Phys.Ther. 113 (1988).

However recent studies of sonophoresis show that application ofultrasound at therapeutic frequencies of about 1 MHz induces growth andoscillations of air pockets present in the keratinocytes of the stratumcorneum disorganizing the stratum corneum lipid bilayers therebyenhancing transcutaneous transport.

This means that permeation using only chemical enhancers andsonophoresis seems to be a limited process, therefore other physicalprinciples must be added to improve the process in order to create amethod for actively and safely enhancing the flux rate of compounds intothe skin to a greater extent than can be achieved without their use.

From now on we will be concerned with ionic permeation, thetransportation of charged particles, then we have to consider thegeneral diffusion equation instead where Fick's First Law must be addedof a second term, an electric potencial gradient term meaning anotherdriving force created by an electrical field applied between the areaunder treatment and a referencial electrode, the so-called process ofiontophoresis.

Electroporation is believed to work in part by creating transient poresin the lipid bilayers of the stratum corneum (Burnett (1989)).

Iontophoresis involves the topical delivery of either an ionized form ofcompound or an unionized compound carried with the water flux associatedwith ion transport, the process being termed electro-osmosis.

An electrical field is created between the area under treatment and areferencial electrode usually fixed to the right wrist of theindividual, normally consisting of a variable electric field withselected properties like amplitude, frequency, waveshape polarity andduty cycle.

The polarity of the electric field depends on the pH of the chemicals tobe delivered into the skin, therefore it must be accordingly selected bythe user.

Low and medium frequency periodic mechanical vibrations created forexample by rotating unbalanced masses applied to the skin surface createmechanical pressure waves that establish a pumping action forcing thecompounds into the skin enhancing the permeation process.

Optimum results are obtained using time varying vibrations, resulting inseveral types of complex waveshapes like “sawtooth”, “triangle”,“on-off” and “staircase” among others, with fundamental frequencies inthe range of 1 Hz to 1 KHz, but with several useful low order harmonicterms having amplitudes, frequencies and phases according to theirrespective expansion using Fourier's series.

Finally, one more physical principles can be used to achieve furtherenhancement of flux rate: constant or time varying magnetic fields whichcan induce mechanical forces to charged particles in such a way to forcethem into the skin the so-called process of magnetophoresis.

It is worthwhile to remember that also some heat is internally generatedby sonophoresis and additionally also iontophoresis contributes withJoule's effect originated heat, all them giving some contribution to theincrease of temperature of the skin, thus some prevision must be made tokeep this temperature under control;

OBJECTS AND SUMMARY OF THE INVENTION

An object of the present invention is to provide a method for fastactive transcutaneous permeation of compounds through the human skintargeting obtaining either local or systemic results allowing,amongothers, the non-invasive painless treatment of cellulitis, localizedfat, stretch marks and flacid skin.

Another object of the invention is to provide a method for the activetranscutaneous permeation of compounds in a non invasive basis, allowingtreatments with minimal occurrence of undesirable collateral effects.

A further object of the invention is to minimize the time of treatmentthrough the synergetic simultaneous use of both chemical enhancers andseveral physical principles.

These and other objects may be accomplished by applying to the skinsurface permeation enhancers and compounds simultaneously with physicalpermeability enhancers such as sonophoresis with modulated ornon-modulated ultrasound continuous or pulsed,iontophoresis;electroporation, mechanical vibrations and magnetophoresis.

Specially designed equipment and application device allowing theapplication of this method will be described herein.

Ultrasound energy also may also open up diffusional pathways in thestratum corneum, causing an increase in the permeability of that layerand causing frictional heat to be generated in deeper tissues,increasing the activity of both lymph and blood circulation, as well asof metabolic processes.

Due to the complete synergism and complementarity of these physicalprinciples their combined actions lead us to fast treatments whenassociated with ultrasound coupling products, chemical permeantsallowing compounds to be efficiently permeated through the skin, sinceboth ultrasound iontophoresis, electroporation, mechanical vibrationsand magnetophoresis force chemical enhancers and compounds into thestratum corneum, thereby reducing the lag time associated with thenon-enhanced (passive) diffusion process.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the distribution of energy fields produced by an ultrasoundtransducer and division into near field (Fresnel field) and far field(Fraunhofer field).

FIG. 2A shows an example of continuous non-modulated ultrasound wave.

FIG. 2B shows an example of pulsed ultrasound wave.

FIG. 2C shows an example of amplitude modulated ultrasound wave.

FIG. 3A shows an example of non modulated electrical field according tothe present invention.

FIG. 3B shows an example of amplitude modulated electrical fieldaccording to the present invention.

FIG. 3C shows an example of frequency modulated electrical fieldaccording to the present invention.

FIG. 3D shows an example of duty cycle modulated electric fieldaccording to the present invention.

FIG. 4A shows an example of “sawtooth” frequency waveshape formechanical vibrations according to the present invention.

FIG. 4B shows an example of “triangle” frequency waveshape formechanical vibrations according to the present invention.

FIG. 4C shows an example of “staircase” frequency waveshape formechanical vibrations according to the present invention.

FIG. 4D shows an example of “on-off” frequency waveshape for mechanicalvibrations according to the present invention.

FIG. 5—Perspective view of an experimental equipment and applicationdevice suitable for the purposes of this invention.

DETAILED DESCRIPTION OF THE INVENTION

Although the present invention, as described herein, presents the bestapproach presently known for enhancing the permeability of membranesusing ultrasound and enhancing the transcutaneous flux rate of acompound through a biological membrane through the use of chemicalpermants and iontophoresis, electroporation, mechanical vibrations andmagnetophoreis, it is to be understood that this invention is notlimited to the particular process steps and materials disclosed hereinas such process steps and materials may vary.

It is also to be understood that the terminology used herein is notintended to be limiting since the scope of the present invention will belimited only by the appended claims and their equivalents.

This invention is intended to establish an optimized mode of delivery ofagents or permeants which exist in the state of the art or which maylater be established as active agents and which are suitable fordelivery by the present invention, including compounds normallydelivered into the body, through body surfaces and membranes, includingskin.

As used herein, a “biological membrane” is intended to mean also thehuman skin.

As used herein, “individual” refers to a human, to which the presentinvention may be applied.

As used herein, “transcutaneous flux rate” is the rate of passage of anycompound, pharmacologically active agent, through the skin of anindividual.

As used herein, “non-invasive” means not requiring the entry of aneedle, catheter, or other invasive medical instrument into any part ofthe body including its natural orifices like mouth, nose, ears, anus,urethra and vagina.

Firstly speaking of permeation of non charged particles, Fick's FirstLaw states that the flux of a compound across the skin can be altered bychanging either the the diffusion coefficient or the driving force, thatis the gradient of concentration.In a simplified way this means that ifthe gradient of concentration is constant, then the transcutaneous fluxrate can only be enhanced by improving the diffusion coefficient. Thiscan be achieved by the use of so-called penetration or chemicalenhancers associated with sonophoresis.

There are two primary categories of components where chemical enhancersare comprised of, that is, cell-envelope disordering compounds andsolvents or binary systems containing both cell-envelope disorderingcompounds and solvents, where the first are well known as being usefulin topical pharmaceutical preparations therefore any cell envelopedisordering compound is useful for purposes of this invention.

Cell-envelope disordering compounds are thought to assist in skinpenetration by disordering the lipid structure of the stratum corneumcell-envelopes;solvents include water; diols, mono-alcohols,DMSO andothers.

European Patent Application 43,738 presents the use of selected diols assolvents along with a broad category of cell-envelope disorderingcompounds for delivery of lipophilic pharmacologically-active compounds.Because of the detail in disclosing the cell-envelope disorderingcompounds and the diols, this disclosure of European Patent Application43,738 is incorporated herein by reference.

Other chemical enhancers, not necessarily associated with binarysystems, include DMSO or aqueous solutions of DMSO such as taught inHerschler, U.S. Pat. No. 3,551,554; Herschler, U.S. Pat. No. 3,711,602;and Herschler, U.S. Pat. No. 3,711,606, and the azones(n-substituted-alkyl-azacycloalkyl-2-ones) such as noted in Cooper, U.S.Pat. No. 4,557,943.

Some chemical enhancer systems may show negative colateral effects suchas toxicity and skin irritation. U.S. Pat. No. 4,855,298 disclosescompositions for reducing skin irritation having an amount of glycerinsufficient to provide an anti-irritating effect.

Since this invention is not drawn to the use of chemical enhancers perse it is believed that all chemical enhancers useful in the delivery ofcompounds through the skin may be associated with sonophoresis,iontophoresis, mechanical vibrations and magnetophoresis in furtherenhancing the delivery of permeants and compounds through the skinsurface.

Permeation through the stratum corneum can occur either byintracellular, intercellular or transappendageal penetration, in thiscase specially through the aqueous pathway of the sweat glands. Theproperty shown by the ultrasound of enhancing the permeability of thestratum corneum and, consequently, increasing transcutaneous flux rateis thought to derive from thermal and mechanical alteration ofbiological tissues.

The physical properties of ultrasound waves that can be changed eitherto control or improve penetration include frequency and intensity alongwith time of application. Other factors are also important, for examplethe composition and structure of the membrane through which moleculesare to be transported, the physical and chemical characteristics of themedium in which the molecules are suspended, and the nature of themolecules themselves.

The exposure may be either continuous or pulsed to reduce excessiveheating of biological membranes, when upper average values of usualintensities in the range of 0.01-2.5 W/cm.sup.2 are used; Selection ismade in such a way to intensity be high enough to achieve the desiredresults as well as low enough to avoid significant increase of skintemperature. However,using our experimental equipment and applicationdevice intensities between 0.3 and 1.5 W/cm.sup.2 have shown to givegood results when the process is associated with simultaneousapplication of iontophoresis.

Used frequencies varied from 20 kHz to 10 MHz, preferably 1 to 5 MHztaking into account that the practical depth of penetration ofultrasonic energy into living soft tissue due to attenuation isinversely proportional to the frequency; high frequencies have beensuggested to improve drug penetration through the skin by concentratingtheir effect in the stratum corneum but frequencies between 1 to 3 MHzshow a better overall efficiency since they create some deeper internalheat producing a temperature rise that speeds up metabolic processes inthe area under treatment.

No significant cavitational effects have been observed in fluids atultrasound frequencies greater than 2.5 MHz, due to the fact that thesecavitational effects vary inversely with ultrasound frequency [Gaertner,W., Frequency dependence of ultrasonic cavitation, J. Acoust. Soc. Am.,26:977-80 (1984)], therefore 2.5 MHz is considered a reasonable estimateof the upper frequency limit for the occurrence of cavitation in fluidsat therapeutic ultrasound intensities.Hence, since cavitation plays animportant role in transcutaneous permeation, the synergistic effect ofsonophoresis and iontophoresis shall be nearly absent with frequencieshigher than 2.5 MHz.

As far as the use of ultrasound for compound delivery is known, resultshave been largely disappointing in that enhancement of permeability hasbeen relatively lower than expected causing no consensus on the efficacyof ultrasound for increasing compound flux across the skin, suggestingthat other driving forces must also be used.

When ultrasound energy is applied into the body using for example acircular plane metallic transducer two fields are created, the nearfield, known as Fresnel field and the far field, known as Fraunhoferfield as shown in FIG. 1.

In Fresnel field ultrasound energy radiated from different parts of theelement travels as spherical waves that interfere both constructivelyand destructively;thus there are zones of maxima and minima ofmechanical pressure along and across the beam. This field ischaracterized by a length L which depends on the radius of the radiantsurface and the wavelenght of the ultrasound in the medium in front ofit, i.e., the skin and soft tissues beneath it.

Therefore the ultrasound energy distribution pattern shows a largenumber of closely spaced local mechanical pressure peaks and nulls. Theenergy is “channeled” into the skin in an structure having parallel“walls” orthogonal to the plane of the transducer face.

In Fraunhofer field the ultrasound beam diverges in such a way whichalso depends on the radius of the radiant surface and the wavelenght ofthe ultrasound in the medium, usually soft tissues, meaning, that inFraunhofer field the energy is spreaded in a conic distribution.

The interface of the piezoelectric transducer with the individual isreflective due to the different values of their respective acousticcharacteristic impedances and energy is reflected back to thepiezoelement. Thus, in order to obtain constructive interference, thatis reinforcement of the ultrasound waves, the thickness of thepiezoelectric transducer, normally circular shaped must be one-halfwavelenght for the frequency used.

In our experiments our application device used a lead zirconate titanatetransducer 2 mm thick, and since the speed of sound for this material isof 4000 m/sec, the frequency which allows maximum energy transfer forsuch device is of 1 MHz.

By many reasons the individual must be mechanically isolated from thepiezoelectric element, and usually this is achieved interposing a plateof material having an intermediate acoustic characteristic impedancebetween them;in order to maximize the energy transfer, this plate musthave a thickness of one quarter wavelenght for the frequency being used.

Our application device used an aluminium plate for this purpose andsince the speed of sound for this material is of 6400 m/s then bestresults were obtained with a plate 1.6 mm thick.

In order to minimize reflexions of the ultrasonic beam, which depend onthe ratio of the acoustic characteristic impedances of the media it iscrossing we must avoid any air gap in the interface between theapplication device and the surface of the skin.Thus a coupling agent,preferably one having a low absorption coefficient of ultrasound energyand being non-staining, non-irritating and slow drying must be topicallyapplied to the skin to efficiently transfer the ultrasonic energy fromthe ultrasound transducer into the skin.

This way the ultrasound coupling agent can be also formulated along withchemical enhancers and drugs to be permeated, the resulting compoundsknown as “melanges”.

The above description shows that each particular application device mustbe operated in a single frequency, otherwise internal acousticmismatches will cause only partial transfer of energy to the individual,decreasing the efficiency of the process.

Besides this, there will be a considerable overheating of the transducercreated by the internal reflected waves, which can negatively affect themechanical integrity of the transducer, as well as causing a degradationof its piezoelectric properties along the time.

Some different patterns of peaks and nulls can be obtained withnon-modulated ultrasound energy mechanically travelling the transducerback and forth on the surface of the area under treatment, since theresults will be quite similar to an “on-off” amplitude modulation,displacing the areas of maxima and minima of pressure along the time.

Application of electric current enhances transcutaneous transport bydifferent mechanisms, for example it provides an additional drivingforce for the transport of charged molecules across the skin sinceelectrical current paths can be established through the intercellularspaces of the cells of the stratum corneum and second, ionic motion dueto application of electric fields may induce convective flows across theskin, referred to as electroosmosis, an important mechanism intranscutaneous transport of neutral molecules during iontophoresis.

Also and it is thought to have additional paths through the salty sweatglands fluids which show a low electrical impedance to the current flowdue to the conductive nature of sweat.

Frequencies can range from 5 KHz to 1 MHz, often in the range of 50 KHzto 100 KHz and rectangular voltage with amplitudes from 0 to 15 V orcurrent waves with amplitudes from 0 to 1.0 mA/cm.sup.2 with properlyselected duty cycles are convenient to achieve good results.

At these frequencies the capacitive reactances of the cells arenegligible compared to their ohmic resistances, therefore the intensityof the current is mostly governed by the ohmic resistance (L. A. Geddes,L. E. Baker, Applied Biomedical Instrumentation, John Wiley & Sons, NewYork,1989).

Therefore current waves obtained through electronic generators havinghigh internal impedance are preferred instead since their amplitudesdon't depend on fluctuactions on the value of skin electrical impedance,allowing safer and more reliable treatments.

Amplitudes shall be kept small enough not to originate either tissueelectrical stimulation or excessive heat due to Joule effect. Goodresults have been obtained with values about 0.5 mA/cm.sup.2.

Mechanical vibrations create pressure gradients which enhance thephysical movement of compounds into the skin, improve both lymph andblood circulation in the area as well as create physical stimuli whichhave a physiological response from the individual, since pressuresensitive nervous terminations of tissues in the area being treated arestimulated and respond to these stimuli increasing the speed of somemetabolic processes.

These pressure waves are inertially created through an unbalancedrotating mass fixed to the shaft of a direct current (DC) micromotorhaving its speed controlled by a pulse width modulation technique (PWM),allowing time varying speeds to be synthesized.

In our experiences several different frequency waveshapes have beenused,i.e., sawtooth, triangle, on-off,staircase, constant low speed,constant high speed periodic switching from low to high speed as well asany combinations of them;all time varying frequency waveshapes havegiven better results, probably due to time varying pressure gradientscreated as well as the property of the individual to have betterperception and responses to changes; of course other waveshapes can beused with the present invention.

Magnetophoresis in based on the law of Electromagnetism which statesthat when charged particles cross a magnetic field they are subject tothe action of forces;thus charged molecules of chemicals being permeatedcan further have a driving force applied to them by means of convenientmagnetic fields having such magnitude, direction and polarity in orderto enhance the process of transcutaneous permeation.

These magnetic fields may be created by the circulation of electriccurrents through specially developed coils placed inside the applicationdevice.

Experimental Equipment and Application Device

In order to have a better understanding of both the equipment and theapplication device created for the purposes of this invention, it willbe described making reference to FIG. 5 where a perspective view isshown.

According to this drawing, the experimental equipment consists of a mainunit comprised of an enclosure (#1), which can be metallic, plastic orusing any other similar materials, which encloses all electroniccircuitry needed for its operation.

At the front part of this main unit (#1) there is a panel (#2) withseveral controls, displays and signaling devices in order to allow aninterfacing with the user as friendly as possible.

The equipment also has a manual application device (#3) made of plastic,metal and/or similar materials connected to the main unit (#1) by anelectrical cable (#4) using an appropriate connector.

A conductive wrist band (#5) is used to connect the main unit to theindividual under treatment through an helicoidal electrical cable.

The application device has an internal ultrasound transducer for thegeneration of 1 MHz ultrasound waves for sonophoresis, mechanicallycoupled to a 35 mm metallic circular plate, designed to achieve bestenhancement in the skin permeability as described herein.

Either iontophoresis and electroporation may be obtained through theapplication of an electric variable field between the metallic surfaceof the application device and the skin, the electric path being closedthrough the conductive wrist band attached to the wrist of theindividual under treatment.

A switch was included in order to reverse the polarity of the electricfield, according to the pH of the melange being used; this switchingaction can be achieved electronically. Amplitude, frequency and dutycycle of a rectangular current wave have were modulated targeting bestresults;also pulsed rectangular waves have been used for the samepurpose.

Amplitudes of currents have been varied in the range of 0.1 to about 1mA/cm.sup.2 with better results obtained for currents higher than 0.5mA/cm.sup.2.

Low frequency mechanical vibrations are generated internally to theapplication device by means of an internal unbalanced rotating mass withspeed controlled through pulse width modulating the DC voltage appliedto the driving electric DC micromotor. Frequencies of 1 Hz to 200 Hzwere used with several speed waveshapes as previously described.

Both constant and variable magnitude magnetic field are generated byelectrical currents passing through a special coil internal to theapplication device.

Since also some spatially distributed internal heat is generated bysonophoresis and also conductive heating is produced by Joule effect atthe face of the metallic plate of the application device, temperature ofthe application device is continuously sensed through a thermal sensorallowing this temperature to be always kept under 41.degree.C, using amicrocontroller and associate electronic circuitry.

This way in normal use some drops of the melange to be permeated intothe skin are topically dispensed and them the application device ismoved in circular patterns over the skin covering the area undertreatment till the complete permeation of the melange is achieved.

Results obtained in treatments of cellulitis, localized fat, stretchmarks and flacid skin with special melanges were encouraging, showingthe validity of both the processes and the method of application used.

The above examples and illustrated embodiments are but representative ofsystems which may be employed in the utilization of one or more chemicaland/or physical enhancement means for the transcutaneous delivery ofpermeants and compounds.

The invention is directed to the discovery that the proper use ofchemical enhancers and ultrasound associated with the simultaneous useof further physical principles through a single application device asdescribed herein enables the noninvasive transcutaneous delivery ofcompounds.

However, the invention is not limited only to the specific illustrationssince there are numerous enhancer systems some of which may functionbetter than another for delivery of permeants and compounds.

Therefore,the invention is limited in scope only by the mentioned claimsand functional equivalents thereof.

1. In a non-invasive method for enhancing the transcutaneous flux rateof an active permeant and either ionized form of compound or anunionized compound into an individual's body surface targeting eitherlocal and systemic results, comprising the steps of (a) contacting anarea with a composition comprising an effective amount of said permeantalong with compounds to be permeated; (b) enhancing the permeability ofthe selected area to the permeant via sonophoresis and applyingsimultaneously to said area iontophoresis, electroporation, mechanicalvibrations and magnetophoresis for a time and with physical propertieseffective to enhance the transcutaneous flux rate into the body; theimprovement comprising; simultaneous application of an active permeantand compounds along with sonophoresis, iontophoresis, electroporationmechanical vibrations and magnetophoresis to an individual's bodysurface area for a time and with physical properties effective toenhance the transcutaneous flux rate into the body, considerablylowering the required time of application compared to that required ifthe chemical enhancers and compounds to be permeated were used alone; 2.The method of claim 1 wherein a chemical permeation enhancer is alsoapplied to the surface of the area under treatment.
 3. The method ofclaim 1 wherein the sonophoresis includes a modulated continuous wave.4. The method of claim 1 wherein the sonopheresis is amplitudemodulated.
 5. The method of claim 1 wherein the sonopheresis includes amodulated, pulsed wave with fixed duty cycle.
 6. The method of claim 1wherein the sonopherisis includes a modulated, pulsed wave with timevarying duty cycle.
 7. The method of claim 1 wherein the sonopherisisincludes a wave that is modulated by a combination of differentmodulation processes.
 8. The method of claim 1 wherein the sonopherisisincludes a non-modulated continuous wave.
 9. The method of claim 1wherein the sonopherisis has-a frequency in the range of about 20 KHz to10 MHz.
 10. The method of claim 1 wherein the sonopheris includes apulsed wave with fixed duty cycle.
 11. The method of claim 1 wherein thesonopherisis includes a pulsed wave with time varying duty cycle. 12.The method of claim 1 wherein the iontophoresis uses an electric fieldranging from 0.1 to 25 V.
 13. The method of claim 1 wherein theiontophoresis uses a time varying electric field.
 14. The method ofclaim 1 wherein the iontophoresis uses some kind of modulation.
 15. Themethod of claim 1 wherein the iontophoresis uses amplitude modulation.16. The method of claim 1 wherein the iontophoresis uses frequencymodulation.
 17. The method of claim 1 wherein the iontophoresis usesduty cycle modulation.
 18. The method of claim 1 wherein theiontophoresis uses a combination of electrical modulations.
 19. Themethod of claim 1 wherein either iontophoresis or electroporation areused.
 20. The method of claim 1 wherein the mechanical vibrations haveconstant frequency.
 21. The method of claim 1 wherein the mechanicalvibrations have frequencies ranging from 1 Hz to 1 KHz.
 22. The methodof claim 1 wherein the mechanical vibrations have time varyingfrequency.
 23. The method of claim 1 wherein the heat generated iscontrolled in such way to keep the skin temperature below 41.degree.C.24. The method of claim 1 wherein the use of magnetophoresis isoptional.
 25. The method of claim 1 wherein the magnetic field isconstant.
 26. The method of claim 1 wherein the magnetic field is timevarying.
 27. The method of claim 1 wherein sonophoresis is supressed.28. The method of claim 1 which further comprises using a plurality oftransducers for applying mentioned physical principles, presenting equalof different physical properties.
 29. The method of claim 1 wherein timeof application is in the range of about 1 to 40 minutes.